MXPA98010667A

MXPA98010667A - Procedure and device to promote the material biological implant

Info

Publication number: MXPA98010667A
Application number: MXPA/A/1998/010667A
Authority: MX
Inventors: Valdes Gonzalez Rafael
Original assignee: Universidad Nacional Autonoma De Mexico
Filing date: 1998-12-15
Publication date: 2000-06-01

Abstract

The present invention relates to a device for promoting implants of biological material, characterized in that it comprises a central porous body, preferably tubular, closing means at the corresponding ends of said porous body, a symbol of diameter and length such that they allow it to be inserted inside the porous body and closure elements, made with a material such that when interacting with the tissues of a living organism, it favors the formation of a fibrocollagen tube on the surface of the pore body.

Description

PROCEDURE AND DEVICE FOR FAVORING THE IMPLANT OF BIOLOGICAL MATERIAL DESCRIPTION OF THE INVENTION TECHNICAL FIELD OF THE INVENTION The present invention relates to the field of biomedicine, particularly with regard to cell implants for the production of biological factors for the treatment of chronic degenerative diseases, as well as the generation of material for tissue implants as splints.

BACKGROUND OF THE INVENTION The deficiency of a biological factor in an individual is the main cause of the appearance of chronic degenerative diseases such as diabetes mellitus, Parkinson's disease, hypothyroidism and others. The traditional treatments of some of these diseases have consisted in the application of deficient biological factors in the individuals or substances that stimulate their production, generally by means of injections of products obtained by chemical or biotechnological way. This type of treatment has several drawbacks, especially in relation to the frequency and dose of administration required to maintain the factor at the optimal level, which is practically impossible to achieve, however it is still the most used method since it is the most important option. easy and economical to carry it out. To improve the bioavailability of the factor, attempts have been made to develop methods, devices and devices for the controlled release of the factor. An alternative refers to dosing pumps of the biological factor depending on the requirement or demand thereof, which, in addition to being complicated, has not been possible to control the dosage since it does not have the means to measure this demand with a certain precision. They have not succeeded.

Another alternative that has been tried is the implantation of cells that produce the biological factor, but the direct contact of the cells with the patient's body provokes a rejection reaction, which is manifested by the formation of tissues that impede the flow of nutrients, with the consequent destruction of the cells, for which the life of the implanted cells is relatively short and the transfer of the biological factors is limited, and consequently their therapeutic effect is deficient. The tissues that appear to reject the implants are made up of cells called lymphocytes, plasma cells and antibodies. Fibrocollagen is the means to cover foreign bodies, even when they are positive. The amount of fibrocollagen produced is relatively high, which is why it is possible to destroy the implanted cells. These tissues, which are formed naturally and could in turn be used as splints for implants in various parts of the body such as blood vessels, urethra, etc., since it is recommended that these splints come from the patient's own tissues, however, currently it has been found that a limitation is that to be effective, a greater availability of the quantity and size of the tissues than those available in the body is required, and there is no method to obtain this type of treatment. useful material for use as a splint. To try to avoid the problems of rejection derived from the direct implantation of cells, a variety of devices have been designed, which generally consist of a camera or capsule where the cells are placed, so that they are isolated and have no contact with the cell. the individual's immune system.

The implant devices containing the cells are generally made of natural polymers such as collagen and alginates, or synthetic polymers such as polyacrylates, vinyl-acrylonitrile, poly-xylene. For example, US Pat. No. 5,614,205 describes a matrix consisting of a poly-para-xylene membrane and a culture of cells that produce insulin for the treatment of diabetes mellitus. The membrane is of certain porosity that allows the passage of nutrients and biological factors, but prevents the passage of immunogenic agents. It is mentioned that biocompatible material does not cause rejection. In US Pat. No. 5,569,462 it is described that the mortality of the cells producing the biological factor of interest is due to the fact that the flows of nutrients and waste are not adequate during the ischemic period of the implant. The proposed alternative consists in using a device with a chamber for cells, where said chamber is immunoisolated with a biocompatible material such as polytetrafluoroethylene (PTFE) of a thickness of 15 microns and porosity of 5 microns. Additionally, the use of immunomodulatory agents such as immunosuppressive agents such as mycophenolic acid, cyclosporin, rapamacyn, etc., or as anti-inflammatory agents such as corticosteroids is required. Given that the ischemic period ends when a good neovascularization is achieved, the inventors propose the use of means for a better neovascularization, such as the use of a substance or cells that promote it or that produce the substance that stimulates it. These devices do not satisfactorily solve the various drawbacks of the aforementioned implants, because despite being biocompatible materials, the tissue formation and inadequate vascularization or around the device continue to exist in relatively short time after implantation, so that the flow blood to the tissues of that region is very low and therefore the availability of nutrients is also low. The construction materials of the devices, although permeable, constitute an additional barrier for the exchange of nutrients and the biological factor between the implanted cells and the patient's body. Furthermore, it is well known that the use of products to reduce the immune response and inhibit the recognition and rejection of transplants and / or implants, such as cyclosporin, have negative effects for neovascularization, thus increasing the probability that the transplant or implant do not succeed.

The Acan patent 5,725,854 claims a method for the treatment of _ diseases comprising the administration of Sertolli cells together with the cells that produce the biological factor. This seeks to create an immunologically privileged site. It is well known that Sertolli cells promote immunological tolerance and contain a high amount of elements to protect the cells that produce the biological factor and to be able to maintain their functioning indefinitely. However, with this alternative, rejection is not completely eliminated, so the administration of immunosuppressants or immunomodulators is still necessary, which in turn has a negative effect on neovascularization. Furthermore, in none of the aforementioned inventions there is established a way to control the amount of fibrocollagen produced, which is precisely the main rejection factor of the implants. That is why it continues to be a necessity to have an effective and efficient way to achieve successful implantation of cells that produce biological factors for the treatment of diseases. It is therefore one of the objects of the present invention to provide a method for developing tissues in a convenient and inexpensive way, which serve both to receive the implant of cells that produce, biological factors or for the treatment of diseases, and to arrange of splints capable of being used as tissue grafts. One of the objects of the present invention is to have means for the formation of natural fibrocollagen tubes of controlled thickness, diameter and length. Another object of the present invention is to provide an isolated site with characteristics that allow good neovascularization for the proper transfer of nutrients and biological factors. Still another object of the present invention is to reduce the use of immunomodulatory substances.

These and other objects will be appreciated in greater detail in the following detailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 represents a general and perspective view of the preferred device for carrying out the process, both according to the present invention. Figure 2 corresponds to one of the preferred embodiments of one of the closure plugs of the device of the present invention. Figure 3 corresponds to the plunger attached to the closure means, in one of the preferred embodiments of the present invention. In the following description of the invention, reference will be made to said drawings for greater clarity thereof.

DETAILED DESCRIPTION OF THE INVENTION In accordance with that shown in Figure 1, it is a device (10), comprising an intermediate section or body (20), preferably porous, through whose interior is located a cavity, the which houses a piston (40), and at whose ends are located sets or closing means (30), which are coupled, one of them, to a first closing element (50), while the corresponding opposite end it is coupled to a second closing element (60), which is joined, at one of its ends, to the plunger (40), in such a way that the device, when closed by means of said second closing plug (60) , keep rigidly inside the porous body (20), said piston (40). It should be mentioned that, according to the method in which said device is used, both according to the present invention, said second closing element (60) can be replaced by another closing element (50) or the like, of such that the cavity that houses the plunger (40) is free, and in this way generate an interior space that is suitable for receiving cells and / or substances for the production of the biological factor intended, all such as may continue to be appreciated to throughout the description of the present invention. The porous body (20) is preferably composed of a cylindrical grid, of the type that can be stainless steel, inert polymer or any other material, capable of giving dimensional stability to the intermediate part of the device assembly (10) and with the necessary porosity inside said device. In accordance with the purposes of the present invention, the degree of porosity of the intermediate porous body (20) of the device, so that it complies with the object of the present invention, should be of a mesh size of 40 to 150 Mesh (frames per square inch). linear inch) in a preferably cylindrical shape. On the other hand, the length of this porous intermediate section or porous body (20) can be the one that is convenient according to the therapeutic needs to adequately propitiate the production of the necessary biological factor, being this length of around 10 to 80 millimeters; however, this length can be considerably longer depending on the type of use that is going to be given to itself, as it can be for obtaining splints, in which case they have lengths around 200 millimeters. For its part, as already mentioned, the intermediate porous body of the device described here is conveniently coupled, at each of its ends, to closure assemblies (30) and their respective elements (50) and / or (60) . It has been determined that the degree of porosity of the grid that forms the intermediate porous body (20), determines, in accordance with the procedure also set forth here and the functions of the patient's organism, the size of the newly formed vessels in the fibrocollagen, for which the mesh or pore size is determined according to the type of application that will be given to the formed fibrocollagen tube. As regards the closing means (30), located on the respective ends of the device (10) of the present invention, they have a preferably tubular section shape, whose length is adequate to be able to perform the closing functions of both sides of said device, and whose proportion, with respect to the porous intermediate body (20), can be 10 to 50% of the length and a diameter similar to said porous body (20). The closing means (30) have, at one of their ends, assembly and holding means, which in this case can be of the preferred form of a medium threaded female type, for the assembly of the closing elements (50) and / or (60). On the other hand, at the opposite end of said closing means, there are connecting elements (31) that allow the corresponding fastening at the corresponding end of the porous body (20), using any means threaded or otherwise. In accordance with one of the preferred modalities of the elements of the device of the present invention, said joining elements (31) preferably consist of a grooved element concentric between the inner and outer walls of the tube where a portion of one of the ends of the porous body (21) is inserted, being attached to the closing means in its connection portion (31), in such a way that the contact pressure between the closing means and the porous body (21) is greater than the tension force caused when the __, closure elements (50) and / or (60) are screwed in and unscrewed. In accordance with that shown in Figure 3, the assembly forming the plunger (40), comprises an element preferably with a section of cylindrical and solid shape, in which, at one of its ends, is coupled the ), which is in turn coupled to the corresponding elements of the porous body (20) and of the closure (30), respectively. For identification purposes, the closing element (60) can have a shape slightly different from that of the closing element (50), in order to be able to identify it with respect to the closing element (50) and remove it according to the use procedure. On the other hand, in the extreme distal or opposite of said plunger (40), is an end of said element, which can have a groove or junction (41) to be coupled to the inner end (53) of the closure element (50) of the coupled assembly of the device of the present invention, in such a way that the plunger (40) is kept completely fixed "inside the porous body (20) and the predetermined separation between both elements is concentrically constant.This embodiment comprises that the length of said plunger (40) is practically equal to the length of the assembly of the porous body (20) with the closing means (30) It is worth mentioning that what is disclosed herein comprises the way in which the piston (40) is sufficiently long that it allows its end (41) to achieve contact and to be coupled to the corresponding means (53) of the element of 100-e. (50), however, good results can also be achieved with a piston whose length is only a part of the length of the porous body, while the diameter of the piston (40) can be practically up to the equivalent of the inside diameter of the piston. porous body (20), however, for better results it is preferred that there be a distance between the inner diameter of said porous body with respect to the outer diameter of said plunger of 1 to 10 millimeters, being the diameter of the piston preferably from 4 to 25 millimeters. The plunger can be solid or hollow, however, the Applicant has found that the use of a hollow plunger presents serious drawbacks, since when the device is placed in the patient body fluid is trapped in the hollow of the plunger that over time presents decomposition and could be the cause of possible infections. In accordance with that shown in Figure 2, the closure element (50) may be in a conventional manner, however, in a preferred embodiment for the best performance of the present invention, said closure element comprises a holding area (51). ), defined by a head preferably of semi-spherical shape; a cylindrical joining area having a fastening means, corresponding to the closing means (30) of the porous body (20), which can be threaded of the male type (52), with a diameter preferably similar to that of said closing means ( 30) to be conveniently coupled thereto; and a concentric fixing zone (53) consisting of a cylindrical element of a preferred diameter of 1 to 4 millimeters but smaller than the orifice of the fixing section (41) of the plunger (40), which constitutes an alignment guide for said plunger in the already coupled assembly of the device of the present invention.For the purpose of coupling and uncoupling, preferably screwing and unscrewing, the closing elements (50) and / or (60) easily, the semi-spherical head of the holding area (51) have a hole, which can be of any geometric shape , in such a way that it facilitates the use of an appropriate tool such as, for example, the use of a key such as the type of nuts, alen type or any other. In the preferred embodiment of the present invention, the fixing area (52) of the closing element (60) and the fixing section (41) of the piston (40), form a one-piece assembly in order that the manipulation of both elements is easier, containing the clamping area (61), an additional support section formed by an elongated element with two parallel side faces and perpendicular to the axis of the closure plug (60) of more than 50% of its length to form a support assembly of the thumb and forefinger to screw and unscrew the assembly into the female thread section of the closure means (30). The length of said support section can be 10 to 40% of the length of the porous body (20). Once in use, the thickness of the generated fibrocollagen tube depends on the separation between the porous body (20) and the plunger (40), so that the separation is determined according to the requirements of use of the fibrocollagen tube. Said separation defines the resistance to collapse of the tube and the uniformity of the fibrocollagen bed. The diameters of the porous body (20) and of the plunger (40) are selected according to the volume and thickness required, from 4 to 35 millimeters, with separation or beam of light from 1 to 10 millimeters. The applicant has found that the thickness of the fibrocollagen tube and the size of the neoformed vessels are important characteristics that provide a site with optimal conditions for the survival of the cells for adequate periods to maintain an effective therapeutic action. The device is manufactured with medical grade materials, these materials for example can be stainless steel, virgin polytetrafluoroethylene (PTFE), titanium, etc. As can be deduced from the description of the device to favor the implantation of biological material, the pieces can be manufactured by machining the threaded parts or by injection into molds, the chosen process being a function of the materials that will be used. In accordance with the present invention, the procedure for the implantation of biological material, in its reservoir mode product of the formation of the biological fibrocollagen tube making use of the aforementioned device, comprises: implantation, in the body of the patient or individual, of the device assembly, with the closing element (60) placed on one of the ends of the porous body, so that the piston (40) is incorporated inside it, thus implanted, by the natural action of the body of the patient, covers fibrocollagen on the porous body (20); then, once the fibrocollagen layer is formed, a partial incision is made in order to expose the part of the device that has the closing element attached to the plunger (60), in order to remove it; when said plunger is withdrawn, a neovascularized fibrocollagen tube results which is convenient for the implantation, through the orifice of the closing element (60), of the cells that produce the biological factor; once said cells that produce the biological factor are implanted, the device is closed, now with a closing element (50), in such a way that the fibrocollagen tube is closed inside the organism. In these terms, the promoter cells of the biological factor act in contact with the newly formed and vascularized tissues, absorbing the biological factor from the bloodstream. In an embodiment of use of the device of the present invention, to be a kind of tissue generating agent for implants, the fibrocollagen tube generated inside the organism of the individual, according to the aforementioned procedure, can be removed without the need to uncouple the closing element with the plunger (60) , but completely removing the device assembly and fibrocollagen tube from the body of the patient or individual, being susceptible and convenient to be destined such tissues as tissue implants or splints. If necessary, the closing elements (50) and (60) and the plunger (40) are removed, whereby the fibrocollagen tube is disposed and immediately proceeds to be implanted in the required place or as intended to be used. The diameter of the device when used as a fibrocollagen tube promoter can range from 4 to 25 millimeters of light and the length is determined by calculation, based on shape needs, when used for splint. When used as a reservoir of biological material, only one of the closure elements (60) is removed with the plunger (40), or the assembly formed by both elements, the biological material consisting of cells that produce the biological factor is injected and optionally a culture medium inside the fibrocollagen tube, in the space left by the plunger (40) and a closure element (50) is installed to prevent the biological material from reaching places where the fibrocollagen tube has not been formed . To increase the effectiveness of the treatment, factor-producing cells manipulated genetically by known techniques can be used. The culture medium that is optionally used is selected depending on the type of cells that are to be implanted. The Applicant has found that with the use of the device of the present invention, semi-insulated sites with good neovascularization are achieved and therefore, the conditions for cell viability are met. Likewise, a good rate of exchange of biological factors is obtained, for example in the treatment of diabetes, observing a better response to the stimulus provided by the level of blood glucose. The number of cells, for the case of the treatment of diabetes referred to in the literature, is 6,000 to 12,000 islets of Langerhans per kilogram of the patient. For the case of the present invention, it has been seen that they can be combined with Sertolli cells to protect them immunologically from rejection. However, in addition to the above, the device can be used to place within the same cells that produce substances with therapeutic activity, such as the case of thyroid and parathyroid cells, among others, without this meaning that the device has effects other than the spirit of the present invention.

Application Examples The device of the present invention was implanted, in its preferred embodiment to favor the implantation of promoter cells of a biological factor, in the dorsal part of a sample of Long Evans rats with weights between 180 and 200 grams. Diabetes was induced by the intravenous application of 65 mg / kg of streptozotocin to the group of ten rats with the device object of the invention and to a control group. The glucose level of both groups showed no significant differences, being of the order of 337 mg / dL. Both groups underwent transplantation of islets of Langerhans isolated and preserved by known conventional techniques, with the difference that the group of rats with device received the islets of Langerhans at the site formed by the device itself. None of the animals were administered immunosuppressive agents. The glucose levels were measured daily during the first week and then once a week. The animals of the control group showed in the first three days a glycemia greater than 250 mg / dL during two consecutive days. The animals of the group with the fibrocollagen tube promoter device showed a significant decrease in the glucose level at levels of 150 mg / dL. Having described the invention, the content is claimed in the following:

Claims

CLAIMS 1. Device for promoting the implantation of biological material, characterized in that it comprises: a central body, preferably tubular; closing means at the corresponding ends of said porous body; a plunger and; Closing elements of the body of the device. Device for promoting the implantation of biological material, according to claim 1, characterized in that the central body is a porous body, preferably based on a grid of cylindrical shape, with mesh size of 40 to 150 mesh and diameter of 5 to 35 millimeters. 3. Device for promoting the implantation of biological material, according to claim 1, characterized in that the porous body contains closure means at its ends, which also have threaded coupling means, preferably of the female type for assembly. . Device for promoting the implantation of biological material, according to claim 1, characterized in that the plunger consists of a cylindrical element with a diameter preferably of 4 to 25 millimeters. Device for promoting the implantation of biological material, according to claims 1 to 4, characterized in that the closure elements consist of a fastening section; a cylindrical union section with a male thread; and, a section of concentric fixation of diameter of 1 to 5 millimeters. Device for promoting the implantation of biological material, according to claims 1, 4 and 5, characterized in that the plunger is connected or forms part of at least one of the closing elements. Device for promoting the implantation of biological material, in accordance with claims 1 to 3, characterized in that the promoter device is made of a sterilizable material. 8. Device for promoting the implantation of biological material, according to claims 1 to 7, characterized in that the space between the piston and the porous body varies according to the thickness of the desired fibrocollagen tube of 1 to 15 millimeters. 9. Procedure for promoting the implantation of biological material, characterized in that it comprises the steps of: implanting in the patient or individual a device for implanting the biological material; observe the formation or deposit of fibrocollagen around said device until a reservoir of neovascularized flbrocollagen is formed; and implant, inside. of the neovascularized fibrocollagen reservoir, cells and / or reactive producers of desired biological factor; 10. Procedure for promoting the implantation of biological material, according to claim 9, characterized in that the substance that produces biological factors is a culture of living cells. 11. Procedure for promoting the implantation of biological material, according to claim 9 and 10, characterized in that the living cells are preferably islets of Langerhans. 12. Procedure for promoting the implantation of biological material, according to claims 9 to 11, characterized in that the substance that produces biological factors contains Sertolli cells. 13. Procedure and device for promoting the implantation of biological material, according to the preceding claims, characterized in that it comprises: implanting, in the body of the patient or individual, the device for the formation of the fibrocollagen tube or reservoir; removing the inner plunger of the device, once said tube or reservoir of neovascularized fibrocollagen is formed; implant the substance that produces the desired biological factor; closing the tube or reservoir of neovascularized fibrocollagen with such an element as to allow a space to exist inside said tube or reservoir of neovascularized fibrocollagen; 14. Procedure and device for promoting the implantation of biological material, according to claim 13, characterized in that the fibrocollagen tube formed can be used as a graft, preferably vascular, trachea, urethra or esophagus, among others.